We aim to synthesize marine metabolites with potential clinical applications. The focus of this research is the synthesis of biologically significant and synthetically challenging natural pyrrole-imidazole alkaloids, in particular, massadine, a newly discovered geranylgeranyltransferase type I (GGTase I) inhibitor. Massadine is a valuable synthetic target because selective GGTase I inhibitors are potential treatments for cancer, cardiovascular disease as well as fugal and viral infection. Toward this end, we have devised a radical cascade cyclization and an oxidative rearrangement reaction to construct the key skeleton of massadine. We will explore the scope and generality of the two approaches. We will utilize these approaches to synthesize massadine and prepare a variety of massadine analogs to facilitate its biological study and clinical evaluation. We believe this research will provide a solution not only to the massadine synthesis, but the synthesis of other oroidin dimers, such as palau'amine, axinellamine, ageliferin and nagelamide. This project serves as our first step toward the construction of both natural and unnatural oroidin dimers with all stereochemical possibilities. We wish to create a focused oroidin dimer library and fill nature's gap in stereochemical diversity. Combining with future collaborative biological studies at UT Southwestern, we wish to help advance oroidin dimer-based drug development. This research program involves development of new chemical methods, which will find applications in pharmaceutical industry. The ultimate goal is to discover new therapeutics using the lessons learned from natural substances.